Ultrasound-induced single-electron reduction of azide groups in aromatic prodrugs

ABSTRACT Ultrasound has emerged as a versatile clinical tool due to its high tissue penetration and ability to deliver energy precisely to targeted areas. Increasing attention is now focused on its ability to induce chemical transformations of compounds in vivo and the underlying mechanisms therein. Here, we report a new ultrasonic chemistry mechanism in which low-intensity ultrasound facilitates the single-electron reduction of aromatic azides, converting them to bioactive amines. This transformation is especially efficient with aromatic compounds bearing strong electron-withdrawing groups or minimal natural charge. Using azide-masked resiquimod (R848-N3) as a model, we demonstrate that ultrasound induces a reduction reaction mediated by β-nicotinamide adenine dinucleotide disodium salt hydrate, with riboflavin tetrabutyrate serving as an electron transfer catalyst, significantly enhancing reaction rates. In a colon cancer model, nanoparticles co-loaded with R848-N3 and riboflavin tetrabutyrate achieved a remarkable 99.0% tumor suppression rate and a 66.7% cure rate when paired with low-intensity ultrasound. This study reveals ultrasound as an effective switch for prodrug activation, laying the foundation for azide-masked compounds as a new class of ultrasound-responsive cancer therapeutics.